Postnatal development produces profound changes in synaptic transmission in the brain. Many developmental studies have focused on changes in the connections between neurons through consolidation or elimination of synaptic connection. Much less is known, however, about the developmental modulation of the strength of synapses, which is also likely to play a critical role in normal neonatal development. This modulation could occur pre-synaptically, or both While several studies have looked at developmental changes in postsynaptic properties, little attention has been paid to developmental changes in presynaptic function. This is an important area since considerable evidence suggests that presynaptic mechanisms are involved in the molecular implementation and maintenance of several types of synaptic plasticity implicated as substrates for learning and memory that are subject to impairment in various forms of mental retardation. Thus, the goal of this proposal is to examine the role of changes in presynaptic function at cerebral cortical excitatory synapses, that utilize the neurotransmitter glutamate, during neonatal development. A unique aspect of this approach is the application of behaviorally salient, natural temporal patterns of activation for testing the dynamic features of neonatal synapses. This proposal describes a series of experiments to determine the developmental regulation of presynaptic function in neonatal hippocampus. Using electrophysiological and pharmacological techniques, developmental changes in synaptic release probability, short- term plasticity, and functional connectivity will be assessed during the first five postnatal weeks. Understanding the normal development of presynaptic properties is a necessary first step to investigating the effects of pre- and postnatal environmental factors, such as maternal malnutrition cause cognitive deficits in short-term memory. Since short-term plasticity is likely to be a cellular substrate for short-term memory, understanding the normal developmental properties of short-term plasticity is a key prerequisite to determining how short-term plasticity and short-term memory are impaired in these different syndromes.